Published online before print August 21, 2009

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(American Journal of Pathology. 2009;175:1187-1199.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081107

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

Stuart J. Ellem^*, Hong Wang^*, Matti Poutanen and Gail P. Risbridger^*

From the Centre for Urological Research,^* Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; and the Turku Center for Disease Modelling, Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland

Prostatitis causes substantial morbidity to men, through associated urinary symptoms, sexual dysfunction, and pelvic pain; however, 90% to 95% of cases have an unknown etiology. Inflammation is associated with the development of carcinoma, and, therefore, it is imperative to identify and study the causes of prostatitis to improve our understanding of this disease and its role in prostate cancer. As estrogens cause prostatic inflammation, here we characterize the murine prostatic phenotype induced by elevated endogenous estrogens due to aromatase overexpression (AROM+). Early-life development of the AROM+ prostate was normal; however, progressive changes culminated in chronic inflammation and pre-malignancy. The AROM+ prostate was smaller at puberty compared with wild-type controls. Mast cell numbers were significantly increased at puberty and preceded chronic inflammation, which emerged by 40 weeks of age and was characterized by increased mast cell, macrophage, neutrophil, and T-lymphocyte numbers. The expression of key inflammatory mediators was also significantly altered, and premalignant prostatic intraepithelial neoplasia lesions emerged by 52 weeks of age. Taken together, these data link estrogens to prostatitis and premalignancy in the prostate, further implicating a role for estrogen in prostate cancer. These data also establish the AROM+ mouse as a novel, non-bacterial model for the study of prostatitis.